Cellular lifespan and senescence: a complex balance between multiple cellular pathways (original) (raw)

A pro longevity role for cellular senescence

GeroScience, 2019

Cellular senescence is a fundamental process that may play positive or detrimental roles for the organism. It is involved in tissue development and in tumor prevention although during aging is becoming a detrimental process contributing to the decline of tissue functions. In previous investigations, we have uncovered a better capacity to detect DNA damage in cells from long-lived mammals. Here, we report that cultured cells derived from long-lived species have a higher propensity to undergo senescence when challenged with DNA damage than cells derived from short-lived species. Using a panel of cells derived from six mammals, which range in lifespan from 3-4 years up to 120 years, we examined cell cycle response, induction of apoptosis

Telomere Shortening as Biological Hallmark of Cellular Senescence and Longevity-An Update

2023

ABSTRACT The process of ageing is the consequence of both genetic and epigenetic alterations associated with metabolic disorders and characterized by mitochondrial dysfunctions generated due to reactive oxygen species. Current reports indicate that cellular ageing or senescence retrograde mitochondrial signaling disorders, telomere shortening, heterochromatin configuration, endoplasmic reticulum strain and unfolded protein responses. Supplemental vitamins, inhibition of cell cycle arrest and controlled expressions of tumor promoting genes p53, p21CIP1 and p16INK4a are robust telomere length longevity promoting interventions and prolong youthful cell functions. This review is aimed to provide an update on the molecular approach mediating the cellular ageing in developmental and programmed replicative ageing cascade with focus on DNA damage response in various cell types. Through rational ideas and critical investigation, we conclude that the combination of irretrievable alternations caused by metabolic reactions elicit the accelerated mechanisms of cellular ageing.

Four faces of cellular senescence

The Journal of Cell Biology, 2011

Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.

Cellular senescence in aging and age-related disease: from mechanisms to therapy

Nature Medicine, 2015

Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy. Aging is the progressive loss of tissue and organ function over time 1. The antagonistic pleiotropy theory of aging proposes that organismal fitness declines, at least in part, because natural selection favors genetic programs that have beneficial effects on reproductive fitness early in life without regard for negative impacts on health at later, post-reproductive ages 2. One set of genes that is likely to qualify as antagonistically pleiotropic is the regulators of cellular senescence 3 , a potent anticancer mechanism that prevents malignancies by permanently withdrawing (pre-) neoplastic cells from the cell cycle 4,5 but also has been implicated as a driver of aging and age-related disease 6-8. The emerging evidence suggests that the drawbacks of senescence are twofold. First, as one might expect, senescence causes a loss of tissue-repair capacity because of cell cycle arrest in progenitor cells. Second, senescent cells produce proinflammatory and matrix-degrading molecules in what is known as the senescence-associated secretory phenotype (SASP).

Cellular Senescence: Mechanisms and Therapeutic Potential

Biomedicines, 2021

Cellular senescence is a complex and multistep biological process which cells can undergo in response to different stresses. Referring to a highly stable cell cycle arrest, cellular senescence can influence a multitude of biological processes—both physiologically and pathologically. While phenotypically diverse, characteristics of senescence include the expression of the senescence-associated secretory phenotype, cell cycle arrest factors, senescence-associated β-galactosidase, morphogenesis, and chromatin remodelling. Persistent senescence is associated with pathologies such as aging, while transient senescence is associated with beneficial programmes, such as limb patterning. With these implications, senescence-based translational studies, namely senotherapy and pro-senescence therapy, are well underway to find the cure to complicated diseases such as cancer and atherosclerosis. Being a subject of major interest only in the recent decades, much remains to be studied, such as regar...

Cellular Senescence as a Therapeutic Target for Age-Related Diseases: A Review

Advances in Therapy

Life expectancy has increased substantially over the last few decades, leading to a worldwide increase in the prevalence and burden of aging-associated diseases. Recent evidence has proven that cellular senescence contributes substantially to the development of these disorders. Cellular senescence is a state of cell cycle arrest with suppressed apoptosis and concomitant secretion of multiple bioactive factors (the senescence-associated secretory phenotype—SASP) that plays a physiological role in embryonic development and healing processes. However, DNA damage and oxidative stress that occur during aging cause the accumulation of senescent cells, which through their SASP bring about deleterious effects on multiple organ and systemic functions. Ablation of senescent cells through genetic or pharmacological means leads to improved life span and health span in animal models, and preliminary evidence suggests it may also have a positive impact on human health. Thus, strategies to reduce ...

Cellular senescence: hot or what?

Current Opinion in Genetics & Development, 2009

The phenomenon of replicative senescence was first observed more than 40 years ago by Hayflick who noted the inability of cultured human fibroblasts to proliferate indefinitely. The recent discovery that cellular senescence is triggered by many different activated oncogenes has led to the notion that senescence, like oncogene-induced apoptosis, serves as a critical and cell-autonomous tumor preventive mechanism. Both the DNA damage response and the ARF tumor suppressor have been mechanistically implicated in oncogeneinduced senescence and the relative contributions of, and potential interactions between, these two pathways remain subjects of a lively debate. More recently, the discovery that cellular senescence can be bypassed during the epithelialmesenchymal transition (EMT) that typically accompanies tumor progression, the observation that organ fibrosis is controlled by cellular senescence and, most noticeably, the mounting evidence linking cellular senescence to inflammation, make cellular senescence a still flaming hot subject after all these years.

Telomeres, oxidative stress and inflammatory factors: partners in cellular senescence?

Longevity & Healthspan, 2014

Senescence, the state of irreversible cell-cycle arrest, plays paradoxical albeit important roles in vivo: it protects organisms against cancer but also contributes to age-related loss of tissue function. The DNA damage response (DDR) has a central role in cellular senescence. Not only does it contribute to the irreversible loss of replicative capacity but also to the production and secretion of reactive oxygen species (ROS), and bioactive peptides collectively known as the senescence-associated secretory phenotype (SASP). Both ROS and the SASP have been shown to impact on senescence in an autocrine as well as paracrine fashion; however, the underlying mechanisms are not well understood. In this review we describe our current understanding of cellular senescence, examine in detail the intricate pathways linking the DDR, ROS and SASP, and evaluate their impact on the stability of the senescent phenotype.

Cellular Senescence and Ageing: Mechanisms and Interventions

Frontiers in aging, 2022

The influence of the activation of a cellular phenotype termed senescence and it's importance in ageing and age-related diseases is becoming more and more evident. In fact, there is a huge effort to tackle these diseases via therapeutic drugs targeting senescent cells named senolytics. However, a clearer understanding of how senescence is activated and the influence it has on specific cellular types and tissues is needed. Here, we describe general triggers and characteristics of senescence. In addition, we describe the influence of senescent cells in ageing and different age-related diseases.